PATENT HIGHLIGHT pubs.acs.org/acsmedchemlett
Endothelial Lipase Inhibitors for the Treatment of Atherosclerosis and Cardiovascular Disorders Ahmed F. Abdel-Magid* Therachem Research Medilab (India) Pvt. Ltd., Jaipur, India Title:
Tricyclic Indole Derivatives Useful Endothelial Lipase Inhibitors
Patent Application Number: WO 2013/123277 A1 Priority Application: US 61/599,066
Publication date: Priority date:
Inventors:
Greco, M.; Ye, H.
Assignee Company:
Janssen Pharmaceutica NV; Tumhoutseweg 30, B-2340 Beerse, Belgium
22 August 2013 15 February 2012
Disease Area:
Atherosclerosis and cardiovascular disorders
Summary:
The invention in this patent application introduces tricyclic indole derivatives, represented generally by formula (I), which possess
Biological Target:
Endothelial Lipase (EL)
activity as endothelial lipase (EL) inhibitors and may potentially be used for the treatment of cardiovascular disorders. Studies have proved an inverse relationship between plasma levels of high-density lipoprotein cholesterol (HDL-C) and the risk for atherosclerosis (a condition in which an artery wall thickens because of the accumulation of fatty materials such as cholesterol and triglyceride) and coronary heart disease (CHD). Endothelial lipase (EL) is a serine-phospholipase that is synthesized in endothelial cells. It is a recently discovered member of the triglyceride lipase family that was first characterized and cloned in 1999. Earlier studies indicated that endothelial lipase catalyzes the hydrolysis of HDL phospholipids and causes the lowering of HDL levels. Studies in mice have established the role for EL in HDL cholesterol regulation. EL knockout mice have shown an elevation in HDL cholesterol levels relative to wild-type mice. Overexpression of the human endothelial lipase gene in the livers of mice markedly reduces plasma concentrations of HDL cholesterol and its major protein apolipoprotein A-1 (apoA-1). Other recent studies suggest that EL may have a pro-inflammatory effect and may be involved in atherogenesis. These findings suggest that inhibition of endothelial lipase is an attractive clinical target for the treatment of cardiovascular disorders. EL inhibitors such as the compounds described in this patent application may potentially be beneficial in elevation of HDL-C plasma levels and consequently the treatment of atherosclerosis and cardiovascular disease. Important Compound Classes:
Definitions:
A represents a 5- to 7-membered saturated ring structure
Key Structures:
The inventors described and listed 28 structures as examples of the compounds of formula (I) including the four representative structures below:
Biological Assay:
Endothelial Lipase Assay (Human/Mouse)
Received: September 14, 2013 Published: September 19, 2013 r 2013 American Chemical Society
1016
dx.doi.org/10.1021/ml400361q | ACS Med. Chem. Lett. 2013, 4, 1016–1017
ACS Medicinal Chemistry Letters Biological Data:
PATENT HIGHLIGHT
The inventors reported the IC50 values (in μM) for the 28 examples. The lowest IC50 values were obtained from compounds 5, 8, and 25 and the highest from compound 28 as listed in the following table:
Synthesis:
The compounds of formula (I) were generally prepared by the reaction of the intermediates V with oxiranes VI in hexafluoro-2propanol followed by dehydration with SO2Cl or POCl3 as illustrated in the following scheme:
Claims:
Claims 1 9: Composition of matter, variations of formula (I) Claims 10 12: Composition of matter, 27 specific examples of the compounds of formula (I) Claims 13 15: Pharmaceutical composition Claims 15 17: Use of compounds in treatments of atherosclerosis, dyslipidemia, low HDL, or high LDL
Recent Review Articles:
1. de Goma, E. M.; Rader, D. J. Nat. Rev. Cardiol. 2011, 8 (5), 266 277. 2. Badellino, K. O.; Rader, D. J. Curr. Opin. Cardiol. 2004, 19 (4), 392 395. 3. Jin, W.; Millar, J. S.; Broedl, U.; Glick, J. M.; Rader, D. J. J. Clin. Invest. 2003, 111 (3), 357 362.
’ AUTHOR INFORMATION Corresponding Author
*Address: 1383 Jasper Drive, Ambler, Pennsylvania 19002, United States. Tel: 215-913-7202. E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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dx.doi.org/10.1021/ml400361q |ACS Med. Chem. Lett. 2013, 4, 1016–1017
